Pratiksha Prabhakar Sangale, Mahesh Hari Kolhe, Rajashree Dadasaheb Ghogare, Gaurao Subhash Damre
The developed 6-HF nanoemulgel demonstrated promising preclinical topical anti-inflammatory efficacy with favourable physicochemical stability. While 6-Hydroxyflavone is a naturally occurring flavonoid with a reported safety profile in preclinical models, direct claims of safety superiority over conventional NSAIDs cannot be made without skin irritation testing, repeated-dose toxicity studies, systemic exposure assessment, and clinical investigation, which warrant further evaluation.
OBJECTIVES: To develop and optimize a 6-Hydroxyflavone (6-HF)-loaded nanoemulgel using a Box-Behnken Design (BBD)-based Quality by Design (QbD) approach for enhanced topical anti-inflammatory activity, addressing the limitations of poor aqueous solubility and inadequate transcutaneous bioavailability of 6-HF.
METHODS: Drug-excipient compatibility was confirmed via the use of preformulation studies such as DSC and FTIR. Pseudo-ternary phase diagrams were built to determine the region of existence of the nanoemulsion. A three-factor, three-level BBD was used to maximize the oleic acid (X1), Tween 80 (X2) and Transcutol P (X3) concentrations, and particle size and PDI were the responses. The optimized nanoemulsion was added to the Carbopol 934 gel bases in four concentrations (0.5-2.0% w/v) to form nanoemulgel batches (NEG1-NEG4), evaluated for physicochemical characteristics, ex vivo skin permeation, and in vivo anti-inflammatory activity using a carrageenan-induced paw oedema model, and in vivo in anti-inflammatory activity using carrageenan induced paw edema model.
RESULTS: The quadratic models demonstrated excellent predictability (adjusted R2 = 0.9851 and 0.9660 for particle size and PDI respectively). The optimized nanoemulsion NF16 exhibited particle size 136.4 nm, PDI 0.211, zeta potential - 26.5 mV, and entrapment efficiency 87.9%. NEG2 (1.0% Carbopol 934) was selected as the optimized nanoemulgel based on superior ex vivo drug release (94.2% at 12 h), balanced viscosity (4256 cP), and spreadability (22.6 g.cm/sec). In vivo studies demonstrated 58.41% paw edema inhibition, statistically comparable to but not superior to standard Diclofenac gel 1% (62.15%) in a carrageenan-induced acute inflammation model Diclofenac gel 1% (62.15%).
CONCLUSION: The developed 6-HF nanoemulgel demonstrated promising preclinical topical anti-inflammatory efficacy with favourable physicochemical stability. While 6-Hydroxyflavone is a naturally occurring flavonoid with a reported safety profile in preclinical models, direct claims of safety superiority over conventional NSAIDs cannot be made without skin irritation testing, repeated-dose toxicity studies, systemic exposure assessment, and clinical investigation, which warrant further evaluation.